Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy (AFFIRM)

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Key information relevant to the recruitment process for the
overall study, such as dates of the recruitment period and locations

Multicenter, global clinical trial

Pre-Assignment Details

Significant events and approaches for the overall study
following participant enrollment, but prior to group assignment

Participants were randomized 2:1 to receive either Enzalutamide or placebo

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Participant Flow: Overall Study

Enzalutamide

Placebo

STARTED

800

399

COMPLETED

254 [1]

163 [1]

NOT COMPLETED

546

236

Lost to Follow-up

1

1

Death

305

211

Withdrawal of consent

9

5

Continuing Treatment

231

19

[1]

Indicates participants continuing long-term follow-up as of 25 September 2011.

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Intent-to-treat population (ITT) included all participants who were randomized into the study.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Survival is defined as time from randomization to death due to any cause. The duration of overall survival was right-censored for participants who were lost to follow-up since randomization or not known to have died at the data analysis cutoff date (this included participants who were known to have died after the data analysis cutoff date).

Time Frame

During study period (up to 3 years)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT included all participants who were randomized into the study.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Measured Values

Enzalutamide

Placebo

Participants Analyzed

800

399

Overall Survival [Units: Months]Median (95% Confidence Interval)

18.4 [1]
(17.3 to N/A)

13.6
(11.3 to 15.8)

[1]

The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment

Statistical Analysis 1 for Overall Survival

Groups [1]

All groups

Statistical Test Type [2]

Superiority or Other

Statistical Method [3]

Log Rank

P Value [4]

<0.0001

Hazard Ratio (HR) [5]

0.63

95% Confidence Interval

0.53 to 0.75

[1]

Additional details about the analysis, such as null hypothesis and power calculation:

No text entered.

[2]

Details of power calculation, definition of non-inferiority margin, and other key parameters:

No text entered.

[3]

Other relevant method information, such as adjustments or degrees of freedom:

Radiographic progression-free survival was defined as time from randomization to the earliest objective evidence of radiographic progression or death due to any cause. Participants were assessed for objective disease progression at regularly scheduled visits. The consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 were taken into consideration for the determination of disease progression. Radiographic disease progression was defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for soft tissue disease, or the appearance of two or more new bone lesions on bone scan. Progression at the first scheduled reassessment at Week 13 required a confirmatory scan 6 or more weeks later. Participants who did not reach the endpoint were right censored at their last assessment.

Time Frame

During study period (up to 3 years)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT included all participants who were randomized into the study.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Time to First Skeletal-related Event [ Time Frame: During study period (up to 3 years) ]

Measure Type

Secondary

Measure Title

Time to First Skeletal-related Event

Measure Description

The time to first skeletal-related event was defined as time from randomization to the occurrence of the first skeletal-related event. Participants were assessed for skeletal-related events at regularly scheduled visits. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. Participants who did not reach the endpoint were right censored at their last assessment.

Time Frame

During study period (up to 3 years)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT included all participants who were randomized into the study.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Measured Values

Enzalutamide

Placebo

Participants Analyzed

800

399

Time to First Skeletal-related Event [Units: Months]Median (95% Confidence Interval)

16.7
(14.6 to 19.1)

13.3 [1]
(9.9 to N/A)

[1]

The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment

Statistical Analysis 1 for Time to First Skeletal-related Event

Groups [1]

All groups

Statistical Test Type [2]

Superiority or Other

Statistical Method [3]

Log Rank

P Value [4]

0.0001

Hazard Ratio (HR) [5]

0.69

95% Confidence Interval

0.566 to 0.835

[1]

Additional details about the analysis, such as null hypothesis and power calculation:

No text entered.

[2]

Details of power calculation, definition of non-inferiority margin, and other key parameters:

No text entered.

[3]

Other relevant method information, such as adjustments or degrees of freedom:

Percentage of Participants Who Were Responders for Functional Assessment of Cancer Therapy-Prostate (FACT-P) [ Time Frame: Baseline up to 3 years ]

Measure Type

Secondary

Measure Title

Percentage of Participants Who Were Responders for Functional Assessment of Cancer Therapy-Prostate (FACT-P)

Measure Description

The FACT-P was a 39-item participant questionnaire which assessed physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and additional prostate cancer specific concerns (12 items). All items were scored from 0 (not at all) to 4 (very much). The sum of scores on all 5 domains constitutes the global FACT-P. The global/total FACT-P score ranged from 0 (worst) to 156 (best), higher scores indicate better health status. Responders were those participants who had a 10-point improvement in their total FACT-P score, as compared with baseline, on two consecutive measurements obtained at least 3 weeks apart.

Time Frame

Baseline up to 3 years

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Evaluable intent to treat (ITT) - all participants who were part of the ITT population and had a global FACT-P score at baseline and at least 1 post-baseline assessment.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Measured Values

Enzalutamide

Placebo

Participants Analyzed

651

257

Percentage of Participants Who Were Responders for Functional Assessment of Cancer Therapy-Prostate (FACT-P) [Units: Percentage of participants]Number (95% Confidence Interval)

43.2
(39.3 to 47.1)

18.3
(13.8 to 23.6)

Statistical Analysis 1 for Percentage of Participants Who Were Responders for Functional Assessment of Cancer Therapy-Prostate (FACT-P)

Groups [1]

All groups

Statistical Test Type [2]

Superiority or Other

Statistical Method [3]

Cochran-Mantel-Haenszel

P Value [4]

<0.0001

Difference in Percentage of Participants [5]

24.9

95% Confidence Interval

18.8 to 30.9

[1]

Additional details about the analysis, such as null hypothesis and power calculation:

No text entered.

[2]

Details of power calculation, definition of non-inferiority margin, and other key parameters:

No text entered.

[3]

Other relevant method information, such as adjustments or degrees of freedom:

Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:

No text entered.

[5]

Other relevant estimation information:

Confidence Interval based on standard normal approximation

5. Secondary:

Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: Baseline and at every study visit from week 13 while on study drug (up to 3 years) ]

Measure Type

Secondary

Measure Title

Time to Prostate-specific Antigen (PSA) Progression

Measure Description

Time to PSA progression was defined as time from randomization to PSA progression. Participants who did not reach the endpoint were right censored at their last assessment or for participants with no post-baseline PSA assessment, date of randomization. For participants with PSA declines at Week 13, the PSA progression date was defined as the date that a >=25% increase and an absolute increase of >=2 nanogram per milliliter (ng/mL) above the nadir was documented, which was confirmed by a second consecutive value obtained 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment). For participants with no PSA declines at Week 13, PSA progression date was defined as the date that a >=25% increase and an absolute increase of >=2 ng/mL above the baseline was documented, which was confirmed by a second consecutive value 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment).

Time Frame

Baseline and at every study visit from week 13 while on study drug (up to 3 years)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

ITT included all participants who were randomized into the study.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Percentage of Participants With Pain Palliation [ Time Frame: Baseline up to 3 years ]

Measure Type

Secondary

Measure Title

Percentage of Participants With Pain Palliation

Measure Description

The proportion of participants with pain palliation was assessed for participants with a stable and sufficient pain burden at study entry. Pain burden was measured by question #3 of the Brief Pain Inventory (Short Form). This scale measures pain on a 0 to 10 scale with 0 indicating no pain and 10 indicating pain as bad as you can imagine. Pain palliation at Week 13 was determined for the proportion of men with baseline bone metastasis(es) who had baseline pain attributable to the metastasis(es). Palliation was defined as >=30% reduction in average pain score at Week 13 compared to baseline without a >=30% increase in analgesic use.

Time Frame

Baseline up to 3 years

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Evaluable ITT Population. Participants with metastatic bone disease at baseline; provided answers to Question #3 of the Brief Pain Inventory – Short Form for a minimum of 4 out of 7 days in the baseline run-in period; stable baseline pain; stable analgesic use; and had an average pain score during the baseline run-in period of ≥ 4.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Participants were evaluable for PSA response rate if they had a PSA level measured at baseline and at least 1 post-baseline assessment. Both PSA responses of > 50% and > 90% were determined. PSA responses required confirmation with a subsequent assessment that was conducted at least 3 weeks later.

Time Frame

During study period (up to 3 years)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Evaluable Intent to Treat. Participants who were part of the ITT Population and had a PSA level measured at baseline and at least 1 post-baseline assessment.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Percentage of Participants With Soft-tissue Objective Response [ Time Frame: During study period (up to 3 years) ]

Measure Type

Secondary

Measure Title

Percentage of Participants With Soft-tissue Objective Response

Measure Description

The best overall soft tissue response as assessed using RECIST v1.1 during the study was summarized using the investigators’ response assessments and also the derived response assessments by treatment group. Only participants with measurable soft tissue disease at screening were included in this analysis. Participants with measurable disease at screening are participants who had at least 1 target lesion identified per RECIST v1.1 at screening. Percentage of participants summarizes the number of participants with complete or partial objective response (%). Soft Tissue assessment based on Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.

Time Frame

During study period (up to 3 years)

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Intent to Treat (ITT) with Measurable Disease. Participants who were part of the ITT Population and had measurable soft tissue disease at screening, defined by at least 1 target lesion according to RECIST v1.1.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

No statistical analysis provided for Percentage of Participants With Soft-tissue Objective Response

9. Secondary:

European Quality of Life Five-Domain (EQ-5D) Scale [ Time Frame: Week 13 ]

Measure Type

Secondary

Measure Title

European Quality of Life Five-Domain (EQ-5D) Scale

Measure Description

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility or index score. Five parameters (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) were assessed on 3-point categorical scale (1= no problems, 2= some/moderate problems and 3= severe problem). Score were transformed and resulted in a total EQ-5D score range of 0 (worst imaginable health state) to 100 (best imaginable health state), with higher scores indicating better health and quality of life.

Time Frame

Week 13

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Evaluable Intent to Treat. Participants who were part of the ITT Population and who were evaluable for EQ-5D.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Measured Values

Enzalutamide

Placebo

Participants Analyzed

126

55

European Quality of Life Five-Domain (EQ-5D) Scale [Units: Units on a scale]Mean (Standard Deviation)

67.2 (19.29)

60.0 (19.26)

No statistical analysis provided for European Quality of Life Five-Domain (EQ-5D) Scale

10. Secondary:

Percentage of Participants With Circulating Tumor Cell (CTC) Conversion [ Time Frame: Baseline up to 3 years ]

CTC conversion was assessed for participants with baseline CTC counts of greater than or equal to (>=) 5 cells per 7.5 milliliter (mL) of blood. A CTC conversion was defined as a decline in the CTC count to less than (<) 5 cells per 7.5 mL of blood. In this outcome measure percentage of participants with CTC conversion was reported.

Time Frame

Baseline up to 3 years

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

CTC Evaluable Population.

Reporting Groups

Description

Enzalutamide

Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.

Placebo

Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the participant was scheduled to initiate a new systemic anti-neoplastic therapy, death, or withdrawal.